Dry powder preparations are used ubiquitously throughout the pharmaceutical, nutraceutical, biotechnological and food industries. Particle engineering often incorporates elements from microbiology, chemistry, formulation science, colloid and interface science, heat and mass transfer, solid state physics, aerosol and powder science, and nanotechnology (Vehring 2007). Processing methods for the production of dry powders include spray drying, spray freeze drying, wet chemistry and phase separation processes, as well as supercritical fluid technologies.
Powder processing technologies are constantly being improved to in an attempt to satisfy increasing demands for more advanced particle engineering. Use of dry powders in specific fields such as respiratory drug delivery, for example, requires powder particles to be within a certain aerodynamic diameter range and possess excellent aerodynamic properties that enable their inspiration into the lungs instead of agglomerating and impacting on the back of the throat where they are retained. Additional characteristics such as rapid dissolution in aqueous lung fluid or through membranes into the blood and emulsification of hydrophobic drug molecules may also be beneficial attributes of an inhalable particle.
Initially, drying technologies served only as crude micronization and solvent-removal methods, and lacked versatility. During the last decade or so, efforts have been undertaken to more completely understand particle formation and control particle morphology. Particle morphology, described by such characteristics as size, shape, internal and exterior structure, and surface properties, is difficult to intentionally design using an empirical approach because of the sheer number of variables involved in the drying process (Vehring 2007). Numerous process variables, such as drying temperature, drying gas flow, nebulizer nozzle parameters, sample solvent, and collection method, are compounded by an almost infinite number of possible formulation components and combinations thereof. To mitigate this task, attempts are being made to derive mathematical equations, computer models, and representative experiments to approximate and predict the thermodynamics, kinetics, and chemical interactions that occur during the drying of a droplet in a spray dryer.
In the case of designing powders for respiratory drug delivery, a particle characteristic of particular importance is aerodynamic diameter, which is defined as the diameter of a unit-density sphere that has the same settling velocity as the measured particle (Vehring 2007). Aerodynamic diameter is useful for approximating the extent of entrainment of a particle in an airflow, and should not be confused with geometric diameter, which is the physical distance across the particle as determined by microscopy. Control of particle aerodynamic diameter during the spray drying process has been found to be partially described by the following equation (Vehring 2007):
                              d          a                =                                                            ρ                P                                            ρ                *                                      6                    ⁢                                                    c                F                                            ρ                *                                      3                    ⁢                                    d              D                        .                                              Equation        ⁢                                  ⁢        1            where da is aerodynamic diameter, ρp is particle density, ρ* is the reference density of 1 g/cm3, CF is the feed solution concentration, and dD is the droplet diameter. It can be seen from Equation 1 that the small aerodynamic diameter required for lung deposition of a particle (1-5 μm) can be controlled by lowering the spray dryer feed solution concentration, by making particles of low density, and/or by decreasing the droplet diameters formed by the spray dryer nozzle. Decreasing the feed solution concentration is often an unattractive option, particularly when scale-up efforts are considered, as it leads to lower product yields during a given timeframe. Achieving small aerodynamic diameters through decreased droplet size and decreased particle density is therefore a superior method for obtaining powders with respirable characteristics.
In addition to controlling the aerodynamic diameter of a particle by lowering its density, irregular surface morphologies can be engineered to maximize the interaction of the particle with an airflow. Pockets, crevices, pores, and other varied surface features allow improved entrainment of a particle in flowing air, imparting significantly improved aerodynamic properties for inspiration into the lungs.
Droplet diameter is largely a function of the performance of the spray dryer nozzle, although certain formulation components that have a large effect on solution properties can also play a role. There are four types of nozzles frequently encountered in spray drying: rotary atomizers, pressure nozzles, two-fluid nozzles (Masters 1972, Sacchetti 1996), and ultrasonic atomizers (Bittner 1999, Freitas 2004). An additional, less common, nozzle that utilizes near-critical or supercritical carbon dioxide will be described presently. Commonly, droplet mass median diameters (MMDs) in pharmaceutical spray dryers range from less than 10 μm to more than 100 μm, producing dried particles with corresponding geometric diameters of 0.5 μm to 50 μm (Vehring 2007).
In contrast to feed solution concentration and droplet diameter, which are dictated by yield requirements and spray dryer design, respectively, particle density has been predominantly controlled by judicious selection of the composition of the formulation. Typically, to obtain powder particles of low density, excipients are added to the feed solution that predispose the drying droplets to form particles that possess either “folded shell” or “solid foam” morphology. Such morphologies contain empty spaces, or voids, within the particle that impart a lower apparent or effective gross density to the particle than that of a solid sphere of identical geometric diameter. Low densities allow particles of larger geometric diameters, which possess superior handling properties such as reduced aggregation and increased dispersibility, to behave aerodynamically as smaller particles that are suitable for respiration into the lungs. Production of very low density particles is therefore desirable and is the focus of current research within the respirable drug delivery field.
Drying of a droplet into a particle with folded-shell morphology is schematically depicted in FIG. 1 (Vehring 2007). Incorporation of formulation excipients that have high Peclet numbers (low mobility within the droplet) causes selective enrichment of that excipient at the surface of the droplet as its boundary recedes during drying. As solvent is progressively removed from the droplet, a shell begins to form at the droplet surface that impedes further reductions in size of the outer diameter. Further solvent evaporation then occurs from near the center of the droplet, causing structural instability that results in buckling of the sphere or complete crumpling.
Excipients that have high Peclet numbers, such as proteins and polymers, are commonly encountered in pharmaceutical powder formulations. Various hollow, dimpled, or wrinkled particle morphologies resulting from the folding-shell drying pathway have been achieved with protein (Vehring, Foss 2007, Maa 1997, Maury 2005, Chew 2001, Maa 1998, Ameri 2006, Samborska 2005), peptide (Zijlstra 2004, Stahl 2002), and polymer (Bittner 1999, Wang 1999, Ting 1992, Baras 2000, Li 2006, Bernstein 1997, Mu 2001, Fu 2001) additives (Vehring 2007). The archetypal shell-forming excipient, leucine, is an excellent shell-former due to its low solubility in aqueous and alcoholic solutions (Vehring 2007), which causes it to reach saturation, precipitation, and a resulting high Peclet number early in the droplet drying process. Because of this, as well as its weak surfactant properties, leucine has been widely used in the spray drying industry to improve flowability and dispersibility of powders (Li 2006, Begat 2005). An example of the change in morphology that can be accomplished with the addition of leucine to a powder formulation is depicted in FIG. 2 (Vehring 2007). Spray-dried immunoglobulin particles form a buckled, folded-shell morphology when the protein is dried alone, as the immunoglobulin protein itself has a high Peclet number (FIG. 2A). However, when leucine is added to the formulation, the particles adopt a wrinkled surface in addition to the buckled, folded shell (FIG. 2B).
Like particles with folded-shell morphologies, particles of solid foam compositions can also possess very low densities due to the presence of internal and/or external voids. However, unlike the process of creating folded shells, spray drying solid foam particles does not rely on excipients with high Peclet numbers. Instead, formulations are designed that incorporate one or more “blowing agents,” volatile additives with high boiling points that serve as “place-holders” within the drying droplet. The blowing agent remains distributed throughout the droplet during drying, and is evaporated or sublimed after most of the droplet drying is complete or during a separate, secondary drying event. Removal of the blowing agent after the particle is dry results in the creation of pores of empty space as the blowing agent evolves from the dried particle matrix. Blowing agents may be volatile salts that sublime upon heating, such as ammonium bicarbonate (Straub 2003) or ammonium carbonate (Narayan 2001), or alternatively, volatile oils. An exemplary case in which a volatile oil has been used to create solid foam particles is PulmoSpheres™, depicted in FIG. 3 (Vehring 2007). PulmoSpheres™ are created from the eventual evaporation of perflubron, a volatile oil that is incorporated into the formulation via an emulsion formed prior to spray drying (Geller 2011).
Although incorporation of certain excipients into the formulation can dispose the droplet drying process to form particles of low density, in many cases it is impractical or undesirable to allow the composition of the powder to be dictated by the necessary inclusion of these additives. In many cases, such as that for the shell-former leucine, the excipient must be included in the formulation in relatively large quantities. For example, in the immunoglobulin example previously noted, it was necessary to incorporate leucine into the particles at 25% of the total weight in order to achieve the desired change in morphology (Vehring 2007). The delivery of immunoglobulin, the active ingredient, would therefore be diminished by a quarter in order to achieve a powder with an improved respirable fraction as compared to pure protein particles. Sacrifices of drug concentration within a particle for the sake of improved aerodynamic properties may be untenable in many situations. Additionally, in the case of respirable drug delivery, each additional excipient must be thoroughly tested for toxicity when inhaled into the lungs, an expensive and time-consuming process.
In addition to contributing to the dilution of active ingredients, the presence of additives that are necessary to obtain desired respirable fractions may be detrimental to the storage stability of the powder. To be physically stable, particles should be created in either a fully crystalline state, or as an amorphous glass with a high glass transition temperature and high viscosity. Particles composed of mixed states, such as partially crystalline or a mixture of polymorphs, exhibit reduced stability due to spontaneous nucleation and growth of the more stable crystalline polymorph. Crystallization during storage of amorphous fractions of a particle often leads to water expulsion and plasticization of the powder (Vehring 2007). Potential incompatibilities among neighboring physical states within the particle increase as the complexity of the formulation increases: the potential for components that spray-dry in crystalline form to negatively impact other components that spray-dry in an amorphous form is higher when the number of additives is large. Likewise, the chemical stability of a particle is partly dependent on any possible reactions among the ingredients, and the potential for a reaction increases with the number of formulation components.
The drawbacks of a complex, multi-excipient formulation can be eliminated if the ideal low-density particles can be created inherently by a novel spray-drying technology itself. Engineering the process to create hollow particles through the physical introduction of voids, irrespective of the formulation, will be of great benefit to the industry, particularly in the field of respiratory drug delivery. Promising methods for the achievement of this goal include the use of supercritical fluid (SCF) technology in the design of new nozzles, with the aim of affecting the atomization of the feed solution stream such that the drying of bubbles, instead of solid droplets, is accomplished. Previous work is schematically represented in FIG. 4 and described in U.S. Pat. No. 6,630,121, incorporated herein by reference in its entirety, in which a Carbon Dioxide-Assisted Nebulization with a Bubble Dryer (CAN-BD) nozzle is employed to mix near-critical carbon dioxide with the feed solution in a low-volume tee. The mixture travels down a 75 μm restrictor and quickly expands to atmospheric pressure in a drying chamber, forming a combination of bubbles and solid droplets. In the drying chamber, dry, warm gas (usually nitrogen) removes the solvent from the bubbles and droplets, and the dried particles are collected on an inline filter to be removed from the gas flow (Sellers 2001). This method has been shown to form a combination of hollow and solid particles (in the absence of shell-forming excipients or blowing agents) with the distribution strongly in favor of solid particles, as illustrated in FIG. 5 (Cape 2008).
However, the use of carbon-dioxide as the nebulizing gas within the nozzle allows for the production of particles with smaller average geometric diameters than the same nozzle configuration with nitrogen as the nebulizing gas, as illustrated in FIG. 6. Nitrogen or air as a nebulizing gas is commonly used in traditional spray dryer nozzles. The small geometric diameters of CAN-BD-produced particles produced by a process in which the carbon dioxide is substituted for nitrogen as the drying gas often translate into small aerodynamic diameters, as predicted by Equation 1, if suitable formulation components are incorporated to enhance dispersibility and hollow particle formation. The CAN-BD process therefore represents an advancement toward the engineering of respirable particles through the precise control of droplet size to create small geometric diameters; however, the process is highly reliant on formulation composition to achieve small particle aerodynamic diameters and dispersible powders. Improvements to the CAN-BD process that allow for the creation of hollow particles, and thus small aerodynamic diameters, irrespective of, will be of great benefit.